Risk of Hypertension Associated with Antivascular Endothelial Growth Factor Monoclonal Antibodies: A Meta-Analysis From 51088 Patients with Cancer

AUTHORS

Weilan Wang # 1 , Le Cai # 1 , Bingkun Xiao 2 , * , Rongqing Huang 2

1 Department of Pharmacy, Medical Supplies Center of Chinese PLA General Hospital, Beijing, China

2 Department of Antiradiation Drug, Beijng Institute of Radiation Medicine, Beijing, China

# These authors are contributed equally as the first author.

How to Cite: Wang W, Cai L, Xiao B, Huang R. Risk of Hypertension Associated with Antivascular Endothelial Growth Factor Monoclonal Antibodies: A Meta-Analysis From 51088 Patients with Cancer, Iran Red Crescent Med J. Online ahead of Print ; 22(7):e100785. doi: 10.5812/ircmj.100785.

ARTICLE INFORMATION

Iranian Red Crescent Medical Journal: 22 (7); e100785
Published Online: July 26, 2020
Article Type: Systematic Review
Received: January 19, 2020
Revised: June 5, 2020
Accepted: June 14, 2020
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Abstract

Context: Hypertension events are the dominant adverse events observed in patients receiving the antivascular endothelial growth factor (anti-VEGF) monoclonal antibodies bevacizumab and ramucirumab treatment, which severe hypertension, particularly hypertensive emergencies, may cause acute target organ injury and major cardiovascular events, that has limited the administration of anti-VEGF monoclonal antibodies. The current meta-analysis aimed to examine the relative risk (RR) of hypertension associated with anti-VEGF monoclonal antibodies.

Evidence Acquisition: PubMed, EMBASE, ASCO Abstracts, ESMO Abstracts, Cochrane Library, and Clinical Trials.gov were searched until July 2019 for relevant phase II and III randomized controlled trials (RCTs). Statistical analyses were performed to examine the RR (with 95% confidence intervals (CIs)) of hypertension associated with the anti-VEGF monoclonal antibodies.

Results: Ninety four RCTs and 51088 patients were included in the current meta-analysis. According to the results, compared with the control arms, anti-VEGF monoclonal antibodies increased the risk of all-grade (RR: 3.45, 95% CI: 2.98 - 4.00) and high-grade (RR: 5.63, 95% CI: 5.05 - 6.26) hypertension. In the subgroup analyses, the risk of high-grade hypertension varied significantly with cancer type, so that the highest RR was for patients with ovarian cancer (17.27, 95% CI: 8.50 - 35.08), whereas the risk of all-grade hypertension did not vary significantly. When stratified based on drug types and drug dose, no significant difference was discovered.

Conclusions: Anti-VEGF monoclonal antibodies significantly increased the risk of hypertension. The risk may vary with tumor type. Clinicians should be aware of the adverse reaction and clinical monitoring as well as effective management of such situations, particularly for high-risk patients.

Copyright © 2020, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited

1. Context

Angiogenesis has an important role in promoting tumor growth, invasion, and metastasis. VEGF-A, one of the members of the vascular endothelial growth factor family, plays a vital role in angiogenesis and tissue neovascularization. Among all receptors, VEGFR-2 is widely considered as the most critical driver of tumor angiogenesis. Therefore, inhibition of angiogenesis via blocking VEGF-A or VEGFR-2 receptor signaling pathway is the key approach in current tumor therapeutics (1).

As a VEGF-A-targeted monoclonal antibody, bevacizumab widely administers in the treatment of various cancers. Ramucirumab is a VEGFR2- targeted monoclonal antibody and inhibits the signaling pathways in endothelial cells that mediate angiogenesis. Ramucirumab is approved for the treatment of advanced gastric, lung, and colorectal cancers.

Hypertension events are the most common adverse events of patients who receive the antivascular endothelial growth factor (anti-VEGF) monoclonal antibodies bevacizumab and ramucirumab treatment, which severe hypertension, particularly hypertensive emergencies may cause acute target organ injury and major cardiovascular events, that has limited the administration of anti-VEGF monoclonal antibodies (2). Previously conducted meta-analyses have investigated the risk of hypertension for bevacizumab or ramucirumab. However, the risk of hypertension caused by the anti-VEGF monoclonal antibodies is not yet evaluated systematically. Therefore, we performed the first meta-analysis to examine the risk of hypertension associated with anti-VEGF monoclonal antibodies.

The current meta-analysis aimed to examine the risk of hypertension associated with anti-VEGF monoclonal antibodies.

2. Evidence Acquisition

2.1. Search Strategy

To conduct the current meta-analysis, using the “bevacizumab”, “Avastin”, “ramucirumab”, “IMC1121B”, “LY3009806”, and “cancer” keywords, the following databases were searched: PubMed, ASCO abstracts, ESMO abstracts, and the clinical trial registration website (https://www.ClinicalTrials.gov) for relevant trials till July 2019. To ensure that all relevant clinical trials are incorporated into the meta-analysis, an independent search was conducted using the Web of Science databases.

2.2. Selection of Trials

The publications and data were reviewed and extracted by two independent investigators. Discrepancies were resolved by consensus with a third researcher. The randomized controlled trials that met the following criteria were included (1) phase II and III randomized controlled trials on cancer patients; (2) having a case group with anti-VEGF monoclonal antibodies treatment alone/concurrent chemotherapy or a control group with placebo/chemotherapy alone; and (3) Events or incidence and sample size available for hypertension.

2.3. Data Extraction

Data on study characteristics, therapeutic strategy, and results and reports of hypertension of all eligible studies were collected. The primary endpoint was the relative risk of hypertension with anti-VEGF monoclonal antibodies. Grading of hypertension events was based on versions 3.0 or 4.0 of Common Terminology Criteria.

2.4. Statistical Analysis

Analyses were performed using the RevMan 5.2. The heterogeneity of eligible studies was assessed by the I2 statistic. If P ≥ 0.1 and I2 ≤ 50%, data were analyzed by the fixed-effects model, the analysis was conducted using the random-effects model. Subgroup analyses were performed separated by the drug type, dosage, and cancer type to explore possible reasons for heterogeneity. We performed a meta-regression analysis to investigate various variables on hypertension events by Stata version 12.0.

3. Results

3.1. Search Results

The initial literature review resulted in 2723 potentially relevant studies, of which 2491 were excluded because of the following reasons: reviews, commentaries, letters, basic studies, case reports, non-randomized controlled trials, irrelevant topics, and duplications. The 232 remaining studies were carefully screened and 138 studies were removed because both control and treatment groups were receiving anti-VEGF monoclonal antibodies or data required for assessment of hypertension were not available. The remaining 94 randomized controlled trials were judged as eligible for the purpose of the analysis (Figure 1).

Outline of the search-flow diagram
Figure 1. Outline of the search-flow diagram

3.2. Characteristics of Studies

94 RCTs and 51088 patients were selected for this meta-analysis, which were as follows 80 trials of bevacizumab (3 - 82) and 14 trials of ramucirumab (83 - 96) were investigated (3 - 82). All malignancies, including lung cancer (19 trials), colorectal cancer (22 trials), breast cancer (19 trials), ovarian cancer (4 trials), pancreatic cancer (2 trials), renal cell cancer (4 trials), gastric or gastro-oesophageal junction adenocarcinoma (7 trials), glioblastoma (3 trials), lymphoma (2 trials), melanoma (2 trials), lymphocytic leukemia (one trial), prostate cancer (one trial), two malignant mesothelioma (one trial), leiomyosarcoma (one trial), urothelial carcinoma (2 trials), hepatocellular carcinoma (one trial), multiple myeloma (one trial), and soft tissue sarcoma (one trial). The quality of all the trials included in the meta-analysis was acceptable. The characteristics of 94 trials are listed in Table 1.

Table 1. Characteristics of Studies Included in the Meta-Analysis
AuthorYearMalignancyPhaseNo in Intervention/ControlConcurrent TreatmentDosemg/kg Per wkNo. Hypertension Events Intervention/Control
All GradeGrade ≥ 3
Bevacizumab
Kabbinavar et al. (3)2003CRCII67/35Fluorouracil + leucovorin2.5 or 513/111/0
Hurwitz et al. (4)2004CRCIII393/397Irinotecan + fluorouracil + leucovorin2.588/3343/9
Kabbinavar et al. (5)2005CRCII100/104Fluorouracil + leucovorin2.532/516/3
Giantonio et al. (6)2007CRCIII287/285Oxaliplatin + fluorouracil + leucovorin5NR18/5
Saltz et al. (7)2008CRCIII694/675Capecitabine + oxaliplatin/Fluorouracil + folinic acid + oxaliplatin2.5NR26/8
Allegra et al. (8)2009CRCIII1326/1321Oxaliplatin + fluorouracil + leucovorin2.5NR159/24
Tebbutt et al. (9)2010CRCIII157/156Capecitabine2.546/196/1
Statopoulos et al. (10)2010CRCIII114/108Irinotecan + fluorouracil + leucovorin2.523/0NR
Guan et al. (11)2011CRCIII141/70Irinotecan + fluorouracil + leucovorin2.5NR4/0
Dotan et al. (12)2012CRCII12/11Capecitabine + oxaliplatin + cetuximab2.56/20/0
de Gramont et al. (13)2012CRCIII1145/1126Oxaliplatin + fluorouracil + leucovorin2.5NR122/12
Bennouna et al. (14)2013CRCIII401/409Fluorouracil/Capecitabine + Oxaliplatin/Irinotecan2.5NR7/5
Cunningham et al. (15)2013CRCIII134/136Capecitabine2.526/73/2
Infante et al. (16)2013CRCII41/39Axitinib + oxaliplatin + fluorouracil + leucovorin2.527/166/6
Cao et al. (17)2015CRCII65/77Irinotecan + fluorouracil + leucovorin5NR8/4
Hegewisch-Becker et al. (18)2015CRCIII156/158None2.528/153/2
Passardi et al. (19)2015CRCIII176/194Irinotecan + fluorouracil + leucovorin/oxaliplatin + fluorouracil + leucovorin2.549/21NR
Koeberle et al. (20)2015CRCIII131/131None2.521/46/1
Kerr et al. (21)2016CRCIII959/963Capecitabine2.5320/7536/6
Snoeren et al. (22)2017CRCIII39/36Capecitabine + oxaliplatin2.5NR9/6
Miller et al. (23)2005BCIII229/215Capecitabine554/541/1
Miller et al. (24)2007BCIII365/346Paclitaxel5NR54/0
Miles et al. (25)2010BCIII499/231Docetaxel2.5 or 5NR13/3
Brufsky et al. (26)2011BCIII458/221Capecitabine/Taxane/Gemcitabine/Vinorelbine5NR41/1
Robert et al. (27)2011BCIII817/403Capecitabine/Taxane/Anthracycline5NR81/4
Martin et al. (28)2011BCII96/89None539/137/1
von Minckwitz et al. (29)2012BCIII956/969Docetaxel5NR25/4
Gianni et al. (30)2013BCIII215/206Docetaxel + trastuzumab5NR25/1
Cameron et al. (31)2013BCIII1288/1271Anthracycline/Taxane5224/4185/5
Coudert et al. (32)2014BCII47/25Trastuzumab + docetaxel54/10/1
von Minckwitz et al. (33)2014BCIII245/238Taxane/Anthracycline/Capecitabine/Vinorelbine/Gemcitabin/Cyclophosphamide569/4233/17
Bear et al. (34)2015BCIII594/596Docetaxel-based chemotherapy5NR62/2
Sikov et al. (35)2015BCII215/218Doxorubicin + cyclophlsphamide ± carboplatin5NR47/4
Earl et al. (36)2015BCIII384/391Docetaxel-Fluorouracil + epirubicin + cyclophosphamide558/428/6
Dieras et al. (37)2015BCII55/56Trebananib + Paclitaxel540/1318/4
Miles et al. (38)2017BCIII238/233paclitaxel574/3126/10
Johnson et al. (39)2004LCII66/32Carboplatin + paclitaxel2.5 or 511/12/1
Sandler et al. (40)2006LCIII427/440Paclitaxel + carboplatin5NR30/3
Herbst et al. (41)2007LCII39/42Docetaxel/pemetrexed56/02/0
Reck et al. (42)2009LCIII659/327Cisplatin + gemcitabine2.5 or 5NR49/5
Herbst et al. (43)2011LCIII313/313Erlotinib5NR15/4
Spigel et al. (44)2011LCII51/47cisplatin/carboplatin + etoposide5NR3/2
Niho et al. (45)2012LCII119/58Carboplatin + paclitaxel557/613/0
Boutsikou et al. (46)2013LCIII116/113Docetaxel + carboplatin ± erlotinib2.55/04/0
Seto et al. (47)2014LCII75/77Erlotinib557/1045/8
Zhou et al. (48)2015LCIII140/134Carboplatin, paclitaxel520/67/1
Pujol et al. (49)2015LCII–III37/37Cisplatin + etoposide ± epidoxorubicin + cyclophosphamide2.518/52/0
Takeda et al. (50)2016LCII50/50Docetaxel520/123/1
Karayama et al. (51)2016LCII45/35Pemetrexed515/67/0
Tiseo et al. (52)2017LCIII95/103Cisplatin + etoposide2.5NR6/1
Wakelee et al. (53)2017LCIII735/738Cisplatin + vinorelbine/docetaxel/gemcitabine/pemetrexed5NR219/60
Spigel et al. (54)2018LCII59/48pemetrexed511/02/0
Yang et al. (55)2003RCCII76/40None1.5 or 515/28/0
Escudier et al. (56)2007RCCIII337/304Interferon alfa588/2811/2
Rini et al. (57)2010RCCIII362/347Interferon alfa5103/1339/0
Donskov et al. (58)2018RCCII59/59Interleukin-2 + interferon-a532/1015/2
Van cutsem et al. (59)2009PCIII296/287Gemcitabine + erlotinib2.560/2610/3
Kindler et al. (60)2010PCIII277/263Gemcitabine5NR28/8
Perren et al. (61)2011OCIII745/753Paclitaxel + carboplatin2.5193/4746/2
Pujade-Lauraine et al. (62)2014OCIII179/181PLD/paclitaxel/topoteca5NR13/2
Aghajanian et al. (63)2015OCIII247/233Gemcitabine + carboplatin5104/2042/2
Coleman et al. (64)2017OCIII330/327Paclitaxel + carboplatin5135/1039/2
Ohtsu et al. (65)2011GCIII386/381Cisplatin + capecitabine2.5NR24/2
Okines et al. (66)2013GCII/III99/101Epirubicin + cisplatin + capecitabine2.5NR1/0
Shen et al. (67)2015GC, GEJCIII100/101Capecitabine + cisplatin2.5NR0/1
Cunningham et al. (68)2017GEJCII/III468/477Epiribicin + cisplatin + capecitabine2.565/334/0
Chinot et al. (69)2014GlioblastomaIII461/450Radiotherapy + temozolomide5181/5752/10
Gilbert et al. (70)2014GlioblastomaIII260/233None5NR11/2
Balana et al. (71)2016GlioblastomaII48/45Temozolomide5NR2/0
Hainsworth et al. (72)2014LymphomaII29/31Rituximab5NR3/0
Seymour et al. (73)2014LymphomaIII395/386Rituximab + doxorubicin + vincristine + cyclophosphamide + prednisone564/14NR
Kay et al. (74)2016lymphocytic leukemiaII33/32Pentostatin + cyclophosphamide + rituximab5NR7/1
Kim et al. (75)2012MelanomaII143/69Paclitaxel + carboplatin5NR5/0
Corrie et al. (76)2014melanomaIII671/672None2.5216/4141/1
Kindler et al. (77)2012MMII53/55Gemcitabine + cisplatin5NR12/5
Zalcman et al. (78)2016MMIII222/224Pemetrexed + cisplatin5125/351/0
Kelly et al. (79)2012Prostate cancerIII504/505Docetaxel + prednisone5NR36/7
Hensley et al. (80)2015uLMSIII52/51Gemcitabine + docetaxel5NR4/0
Chisholm et al. (81)2017STSsII71/79Cyclophosphamide + Vinorelbine2.5NR0/0
White et al. (82)2013multiple myelomaII50/50Bortezomib511/28/0
Ramucirumab
Garon et al. (83)2014LCIII627/618Docetaxel3.368/3035/13
Doebele et al. (84)2015LCII67/69Pemetrexed + carboplatin/cisplatin3.313/47/1
Yoh et al. (85)2016LCII76/81Docetaxel3.36/04/0
Petrylak et al. (86)2016UCII46/45Docetaxel3.311/33/0
Petrylak et al. (87)2017UCIII258/265Docetaxel3.329/1215/5
Tabernero et al. (88)2015CRCIII529/528Irinotecan + fluorouracil + leucovorin4138/4559/15
Moore et al. (89)2016CRCII52/49Oxaliplatin + fluorouracil + leucovorin415/17/1
Mackey et al. (90)2015BCIII752/382Docetaxel3.3203/4451/7
Yardley et al. (91)2016BCII69/65Eribulin3.39/13/1
Vahdat et al. (92)2017BCII52/49Capecitabine3.316/14/1
Fuchs et al. (93)2014GC or GEJCIII236/115None438/918/3
Wilke et al. (94)2014GC or GEJCIII327/329Paclitaxel478/1646/8
Yoon et al. (95)2016GC, EC,or GEJCII82/80Oxaliplatin + fluorouracil + leucovorin431/1013/3
Zhu et al. (96)2015HCIII277/276None456/2035/10

Abbreviations: BC, breast cancer; CRC, colorectal cancer; EC, esophagus cancer; GC, gastric cancer; GEJC, gastroesophageal junction cancer; HC, hepatocellular carcinoma; LC, lung cancer; MM, malignant mesothelioma; NR, not reached; OC, ovarian cancer; PC, pancreatic cancer; RCC, renal cell carcinoma; SCCHN, squamous cell carcinoma of the head and neck; STSs, soft tissue sarcomas; UC, urothelialcarcinoma; uLMS, uterine leiomyosarcoma.

3.3. RR of All-Grade Hypertension Events

To assess the relative risk of all-grade hypertension 58 RCTs were reviewed. The random-effects model (I2 = 72%) revealed that anti-VEGF monoclonal antibodies significantly increased the relative risk of all-grade (3.45, 95% CI: 2.98 - 4.00, P < 0.00001) hypertension compared to control arms (Figure 2).

Forest plot of the relative risk of all-grade hypertension
Figure 2. Forest plot of the relative risk of all-grade hypertension

3.4. RR of High-Grade Hypertension Events

The relative risk of high-grade hypertension was assessed by 91 RCTs. Using a fixed-effects model (I2 = 46%), anti-VEGF monoclonal antibodies significantly increased the relative risk of high-grade hypertension (5.63, 95% CI: 5.05 - 6.26, P < 0.00001) (I2 = 46%). (Figure 3).

Forest plot of the relative risk of high-grade hypertension
Figure 3. Forest plot of the relative risk of high-grade hypertension

3.5. Subgroup Analysis According to Drug Type

To explore the association between risk of hypertension events and drug type, a subgroup analysis was performed according to the type of the administered drug, which indicated the relative risk of all-grade hypertension events for bevacizumab (3.57: 95% CI: 2.98 - 4.28, P < 0.00001) and for ramucirumab (2.92: 95% CI: 2.42 - 3.52, P < 0.00001). No significant difference was observed between the subgroups (P = 0.571, Table 2).

Table 2. Relative Risk of All-Grade Hypertension Associated with Angiogenesis Inhibitors in the Subgroup Analysis
HypertensionNumber of TrialsNumber of Events/TotalRR, 95% CIPP Value for Group Difference
Treatment Control
Type of drug0.571
Bev442853/10487738/101853.57 [2.98, 4.28]< 0.00001
Ram14711/3450196/29512.92 [2.42, 3.52]< 0.00001
Drug dosage, mg/kg/week0.408
Bev 2.5191232/4773351/48033.13 [2.51, 3.91]< 0.00001
Bev 5271620/5677389/54494.06 [3.09, 5.34]< 0.00001
Ram 3.38355/194795/15742.53 [2.02, 3.17]< 0.00001
Ram 46356/1503101/13773.21 [2.46, 4.18]< 0.00001
Tumor types0.074
OC3432/132277/13136.15 [3.34, 11.35]< 0.00001
RCC4238/83453/7504.02 [2.35, 6.87]< 0.00001
Other tumor512894/11781804/110733.23 [2.76, 3.76]< 0.00001

Abbreviations: Bev, bevacizumab; OC, ovarian cancer; Ram, ramucirumab; RCC, renal cell carcinoma.

For high-grade hypertension events, the relative risk (RR) was 6.04 (95% CI: 5.37 - 6.80, P < 0.00001) for bevacizumab and 3.83 (95% CI: 2.96 - 4.96, P < 0.00001) for ramucirumab. There was no significant difference (P = 0.224) between bevacizumab and ramucirumab (Table 3).

Table 3. Relative Risk of High-Grade Hypertension Associated with Angiogenesis Inhibitors in the Subgroup Analysis
HypertensionNumber of TrialsNumber of Events/TotalRR, 95% CIPP Value for Group Difference
TreatmentControl
Type of drug0.224
Bev771970/22533296/207816.04 [5.37, 6.80]< 0.00001
Ram14300/345068/29513.83 [2.96, 4.96]< 0.00001
Drug dosage, mg/kg/week0.369
Bev 2.530619/9562104/94615.70 [4.66, 6.97]< 0.00001
Bev 5511351/12934201/119456.16 [5.34, 7.11]< 0.00001
Ram 3.38122/194728/15743.39 [2.26, 5.08]< 0.00001
Ram 46178/150340/13774.17 [2.98, 5.83]< 0.00001
Tumor types0.003
OC4140/15018/149417.27 [8.50, 35.08]< 0.00001
RCC473/8344/75013.29 [5.44, 32.50]< 0.00001
Other tumors832057/23648352/214885.27 [4.72, 5.88]< 0.00001

Abbreviations: Bev, bevacizumab; OC, ovarian cancer; Ram, ramucirumab; RCC, renal cell carcinoma.

3.6. Subgroup Analysis According to Drug Dose

In the stratified analysis, which was performed according to the dose of anti-VEGF monoclonal antibodies, RR of all-grade hypertension for bevacizumab at 2.5 mg/kg/week was 3.13 (95% CI: 2.51 - 3.91), for bevacizumab at 5 mg/kg/week was 4.06 (95% CI: 3.09 - 5.34), for ramucirumab at 3.3 mg/kg/week was 2.53 (95% CI: 2.02 - 3.17), and for ramucirumab at 4 mg/kg/week was 3.21 (95% CI: 2.46 - 4.18). No significant difference was found by various drug doses (P = 0.408, Table 2).

For high-grade hypertension events, RR for bevacizumab at 2.5 mg/kg/week was 5.70 (95% CI: 4.66 - 6.97), for bevacizumab at 5mg/kg/week was 6.16 (95% CI: 5.34 - 7.11), for ramucirumab at 3.3mg/kg/week was 3.39 (95% CI: 2.26 - 5.08), and for ramucirumab at 4 mg/kg/week was 4.17 (95% CI: 2.98 - 5.83). No significant difference was observed by various drug dose (P = 0.369, Table 3).

3.7. Subgroup Analysis According to Cancer Type

In the subgroup analysis, which was performed according to the cancer type (i.e., ovarian cancer, renal cell carcinoma, and other cancer types), the risk of all-grade hypertension events was higher for these cancers. RR for ovarian cancer patients was 6.15 (95% CI: 3.34 - 11.35), for renal cell carcinoma patients was 4.02 (95% CI: 2.35 - 6.87), and for other tumor patients was 3.23 (95% CI: 2.76 - 3.76). However, RR of all-grade hypertension events did not vary significantly according to the cancer type (P = 0.074, Table 2).

For high-grade hypertension events, RR varied significantly (P = 0.003), the highest and lowest RR was for ovarian cancer patients (17.27, 95% CI: 8.50 - 35.08) and for other cancer patients (5.27, 95% CI: 4.72 - 5.88, Table 3), respectively.

3.8. Publication Bias

Funnel plots were performed to assess publication bias. No apparent publication bias was detected for all-grade and high-grade hypertension by the funnel plots.

4. Discussion

To the best of our knowledge, this is the first meta-analysis that examined the risk of hypertension events associated with anti-VEGF monoclonal antibodies.

Analysis of the data from RCTs demonstrated that anti-VEGF monoclonal antibodies increase the risk of all-grade (RR: 3.45, 95% CI: 2.98 - 4.00) and high-grade (RR: 5.63, 95% CI: 5.05 - 6.26) hypertension compared to control arms. The mechanisms of hypertension induced by angiogenesis inhibitor included increasing cell apoptosis, decreasing endothelial renewal capacity, suppressing the production of nitric oxide in vessels, and decreasing the number of capillaries and arterioles (2).

Because severe hypertension, particularly hypertensive emergencies, may cause acute target organ injury and major cardiovascular events, which in turn leads to limited administration of the anti-VEGF monoclonal antibodies. So, clinical monitoring and effective management might be important ways for the safe application of these agents.

To explore possible risk factors, subgroup analysis was performed according to the types of administered drugs. In the current meta-analysis, there was a higher risk of high-grade hypertension in patients using bevacizumab compared with ramucirumab (RR: 6.04 VS 3.83). However, no significant difference (P = 0.224) was discovered between bevacizumab and ramucirumab.

As a VEGF-A-targeted monoclonal antibody, bevacizumab prevents the activation of VEGFR-1 and VEGFR-2, whereas ramucirumab only inhibits the VEGFR-2 receptor. VEGFR-2 is a critical receptor for angiogenesis, and blockade of the VEGF-A/VEGFR-2 signaling may result in endothelial dysfunction and hypertension (2). The precise mechanism of VEGFR-1 is not entirely understood, and the study showed that VEGFR-1 tyrosine kinase signaling also had an effect on angiogenesis (97). Blockade of the VEGF-A/VEGFR-1 signaling resulted in the endothelial dysfunction and hypertension, but simultaneously played only a minor role compared with VEGF-A/VEGFR-2 signaling (98). This may be the reason for the higher risk of high-grade hypertension in patients who were receiving bevacizumab compared to those who were receiving ramucirumab; however, the difference was not statistically significant. The difference between bevacizumab and ramucirumab was more obvious for the risk of ATE, VTE, and high-grade bleeding (99).

Based on the results, all doses of angiogenesis inhibitors increase the risk of all-grade and high-grade hypertension events, but no significant difference was found between various doses of antiangiogenic monoclonal antibodies bevacizumab (2.5 mg/kg/week and 5 mg/kg/week) and ramucirumab (3.3 mg/kg/week and 4 mg/kg/week), no matter for the risk of all-grade hypertension (P = 0.408) or the risk of high-grade hypertension (P = 0.369), suggesting that the risk of hypertension events may not be dose-dependent.

In a meta-analysis on angiogenesis inhibitors, patients with renal cell carcinoma or ovarian cancer had a high risk of hypertension. Therefore, we performed subgroup analysis according to renal cell carcinoma, ovarian cancer, and other cancer types to identify potential risk factors. The risk of high-grade hypertension varied significantly according to the cancer type, with the highest and lowest RR was for ovarian cancer and other types of cancer. The underlying mechanisms of these differences are still unclear. A possible explanation is that patients with hypertension were not excluded from ovarian trials, despite antihypertensive treatment. Also, hypertension events are relatively common in women with ovarian cancer. The high incidence rate of hypertension may be related to cancer or its ovariectomy treatment. The depletion of endogenous estrogen by ovariectomy, at least in part, induces hypertension. For example, at least 40% of the participants of the OCEANS trial had baseline hypertension, and according to the literature, pre-existing hypertension predicts the increased risk for anti-VEGF therapy-induced hypertension (63). Besides, the RR of patients with renal cell carcinoma was times higher than those with other cancers. Although nephrectomy performed among renal cell carcinoma patients can decrease glomerular filtration, the concentration of antiangiogenic monoclonal antibodies is not be influenced by a decreased GFR likely, because the metabolism and elimination of these agents primarily rely on proteolytic catabolism throughout the body, and does not depend primarily on elimination through the kidneys and livers (2, 100). Thus, the possible explanation for this phenomenon is that post nephrectomy glomerular hypertrophy may be more dependent on VEGF to keep structural completeness than a normal kidney, leading to increased sensitiveness to angiogenesis inhibitors (101). So, patients with ovarian cancer or renal cell carcinoma should pay more attention to hypertension when receiving antiangiogenic monoclonal antibodies.

4.1. Limitations

One limitation of this meta-analysis is that we conducted subgroup analysis only for ovarian cancer, renal cell carcinoma, and other cancer types, mainly because it was difficult to assess so many cancer types included in the current meta-analysis. Besides, except for drug type, drug dose, and cancer type, other potential risk factors, such as age, race, sex, and treatment duration, could increase clinical heterogeneity and, therefore, were not evaluated in the study. Finally, the literature search was limited to articles published in English, which may have led to selection bias.

5. Conclusions

In conclusion, the results showed that anti-VEGF monoclonal antibodies significantly increased the risk of hypertension. The risk may vary with cancer type, in which the highest RR was for patients with ovarian cancer (17.27, 95% CI: 8.50 - 35.08). When patients were stratified based on the type of administered drugs and dosage, no significant difference was observed. Clinicians should be aware of the adverse reaction and clinical monitoring as well as effective management of such situations, particularly for high-risk patients.

Footnotes

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